National Human Genome Research Institute

National Institutes of Health U.S. Department of Health and Human Services

Background on Ethical and Sampling Issues Raised by the International HapMap Project

October 2002

Members of the research consortium working on the International HapMap Project have taken steps to try to ensure that the map will be designed, developed and used in a manner that is sensitive to the ethical, legal and social concerns raised by this type of genomics research.

Since its inception in 1990, the Human Genome Project has paid special attention to the complex ethical, legal and social implications of this kind of research. In keeping with this practice, the National Human Genome Research Institute (NHGRI) established a group consisting of geneticists, social scientists and experts on the ethical and societal implications of genetic research to address a number of aspects of the project. These included how to design the most scientifically valid sampling strategy, how to engage the individuals and communities that will be asked to provide samples, how to describe the populations, and how to minimize the chance of misunderstanding or misuse of the results of future studies that will rely on the HapMap.

This group, which was co-chaired by David Valle, M.D., of Johns Hopkins University, Ellen Wright Clayton, M.D., J.D., of Vanderbilt University and Lynn Jorde, Ph.D., of the University of Utah, proposed a strategy for the HapMap project designed to meet both the need for high quality, scientific research and the need for the project to adhere to the highest ethical standards to protect participants.

Sampling Strategy

The HapMap will be a new tool to speed the discovery of genetic contributions to diseases. The HapMap will describe the common patterns of human genetic variation and will be used in future studies that compare the patterns of genetic variation (haplotypes) in people with a specific disease to patterns in people who do not have the disease. By identifying regions in the genome showing differences in the haplotype patterns, researchers can focus their studies on those genomic regions to more efficiently find the particular genetic variants that contribute to the disease.

The HapMap project will begin with sample collection. Research groups will collect blood samples from a total of 200 to 400 people from four large, geographically distinct populations. These populations are: the Yorubas in Nigeria; the Japanese; the Han Chinese; and U.S. residents with ancestry from northern and western Europe. Except for the U.S. samples, all of the samples will be newly collected for this project. The U.S. samples, which already exist, will be used only after the donors provide a new and specific consent for the HapMap project.

These four populations were selected to include people with ancestry from widely separate geographic regions. Researchers have found that most human populations share the common haplotype patterns. Research already suggests that the overall organization of genetic variation is similar in all four populations, but that there will be enough differences in haplotype frequencies to justify genome-wide studies of samples from these populations.

Because populations have similar haplotype patterns, the project will not have to examine all of the world's thousands of populations to make the HapMap useful for studies relating genetic variation to disease in any population. Additional research is underway to confirm whether the common haplotypes in other populations really will be found in the four populations being studied for the HapMap. If needed, more populations could be added to the HapMap to ensure that the map is broadly useful.

The four populations chosen to develop the HapMap initially are neither typical nor well-defined. None of the populations should be considered representative of all populations on the same continent. For example, the Yoruba samples studied for the HapMap are not representative of all Africans, or even of all West Africans.

The purpose of the HapMap and its sampling strategy make this project very different from the Human Genome Diversity Project (HGDP), an anthropologically oriented effort proposed more than a decade ago that was designed to learn about human population history and the biological relationships among human populations. The HGDP would have studied genetic variation "to see if, for example, the Irish are more closely related to the Spaniards or to the Swedes," according to the project's material. A number of groups representing indigenous peoples were concerned that the project would exploit vulnerable individuals and populations. They also objected to the HGDP's potential intrusion into cultural beliefs about population origins. Ultimately, and in large measure because of the criticisms, the HGDP was never carried out.

Unlike the HGDP, the HapMap's goal is biomedical: to create a resource that can be used in many future studies of health and disease. In addition, unlike the HGDP, which would have studied primarily small, isolated populations, the International HapMap Project will study only large, less vulnerable populations.

Informed Consent and Privacy

Obtaining meaningful informed consent from people who are donating DNA samples for the HapMap project raises complex challenges. The international researchers collecting the samples are devoting considerable effort to figuring out how best to translate complex information about genetics and haplotypes into language that ordinary people can understand. Researchers must be sensitive to cultural norms surrounding decision-making within families and communities, and to beliefs about the relationships among genetics, kinship and group identity.

All donors will be asked to give consent for their samples to be used not just for the HapMap itself, but also in many types of future genetic variation studies. Such studies may examine how genes are regulated, the biology of DNA, how new variations arise and the genetic history of human groups. Researchers will explain to donors that the benefits of the HapMap and of other genetic variation research may not become apparent for some time and that the donors themselves may not directly benefit from participating.

Before obtaining consent from the individual donors, researchers will initiate a process of community engagement. People in these communities will provide advice about the informed consent process, as well as how samples from their community will be collected, described and used. A community advisory group will be established for each sampled community to serve as liaison between the people in that community and the repository where the samples will be stored. These groups will monitor future uses of the samples to make certain that these future uses are consistent with the informed consent form.

The blood samples used to make the HapMap will be collected without any medical or personally identifying information about the donors. In a further step to ensure the complete anonymity of the donors, more samples will be collected than will actually be used, which means that no one, not even the donors themselves, will ever know for sure whose samples were used to develop the HapMap.

Genetic Discrimination and Determinism

Because researchers will not collect medical or personally identifying information, there is virtually no risk that the HapMap itself will lead to discrimination against any of the individual sample donors. However, in future studies, some genetic variants will be identified that promote wellness and protect against disease, while other variants will be identified that increase the risk for particular diseases. When researchers use the HapMap and find that a disease is associated with a genetic variant that is common in a particular population, some people may mistakenly generalize that all individuals in that population have increased risk for the disease or that the population as a whole is somehow genetically inferior.

Another problem with the interpretation of genetic variation is assuming that "genetic" means "unchangeable," and that because someone has a particular genetic variant they are "doomed" to get the disease. These incorrect assumptions are called genetic determinism. Genetic determinism overlooks the strong contributions that environmental factors make to diseases and that there may be ways to reduce the risk of getting those diseases. So, even though people may have genetic variants contributing to their risk of a disease, many of them will never get the disease.

Genetic discrimination and genetic determinism are both potential problems that can arise from any association study in which researchers relate genetic variation to disease risk. These potential problems are not unique to studies that will use the HapMap. Nevertheless, the HapMap consortium intends to make concerted efforts to reduce the risk of such problems. Among the steps the group plans to take are:

Educating the public and researchers about what the results of genetic studies in general, and association studies in particular, mean and do not mean -- with the focus on differences in genetic risk among individuals within a population, not among populations. An association study compares a haplotype pattern in individuals with a disease to individuals who do not have the disease to find the genes directly associated with the condition.

Educating researchers to design their studies and describe their results carefully. For example, researchers should describe the studied population accurately; they should also report how much of the risk for a disease can be attributed to genetic variants and how such variants interact with environmental factors. Where these matters are not well understood, uncertainty should be acknowledged.